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Updated: Aug 13, 2026
09:22
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau
Fei Sun1,2, Yang Liu3,4, Qiuzhi Zhou1,5
1Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 11, 2026
Summary
A novel drug, TP2, effectively reduces toxic Tau protein buildup in Alzheimer's disease models. This therapeutic candidate restores neuronal function and reverses cognitive decline by targeting pathological phosphorylation.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Hyperphosphorylated Tau (p-Tau) accumulation drives neurodegeneration in Alzheimer's disease (AD).
- Existing Alzheimer's therapeutics face limitations in addressing Tau pathology.
- Targeting Tau phosphorylation represents a key therapeutic strategy for AD.
Purpose of the Study:
- To develop and evaluate TP2, a novel small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC).
- To investigate TP2's mechanism of action in reducing p-Tau.
- To assess TP2's therapeutic efficacy in preclinical tauopathy models.
Main Methods:
- TP2 was designed to link Protein Phosphatase 2A (PP2A) to Tau, promoting targeted dephosphorylation.
- TP2's efficacy was tested in P301L and AAV-hTau-N368 tauopathy mouse models.
- Assessments included measuring brain p-Tau levels, Tau aggregates, neuronal morphology, synaptic integrity, and cognitive function.
Main Results:
- TP2 administration significantly reduced brain p-Tau levels, oligomers, and neurofibrillary tangles.
- TP2 treatment preserved neuronal morphology, synaptic integrity, and microtubule stability.
- Cognitive deficits were robustly reversed in multiple behavioral tests following TP2 treatment.
Conclusions:
- TP2 effectively targets upstream pathological Tau phosphorylation.
- TP2 demonstrates significant therapeutic potential for halting neurodegeneration in Alzheimer's disease.
- TP2 represents a promising candidate for restoring cognitive function in tauopathies.
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